Hepatitis C Virus (HCV) causes a persistent infection in most humans exposed to the virus. HCV infection in time can lead to cirrhosis and hepatocellular carcinoma. Although the annual number of newly infected patients has dropped significantly over the past decade, about 4 million people are currently persistently infected in the USA. There is presently no universal drug available to treat HCV infections. The current treatment regimen for HCV is based on a combination of pegylated interferon and ribavirin. However, even this improved combination of drugs is not able to clear HCV in all patients. About 50% of patients do not respond to the treatment. Even more problematic is that, based on the state of their liver disease, some patients cannot be treated with interferon, as this will enhance the disease. In addition, some genotypes have shown particular resistance to interferon/ribavirin treatment. Experience obtained from drug development with other RNA viruses has shown these viruses readily generate variants that show resistance to protease and polymerase inhibitors. The long-term goal of our research is to develop HCV-specific phosphorodiamidate morpholino antisense oligomer (PMO) drugs targeting replication and translation signals. The specific aims proposed are to design and assess the efficacy of antisense PMO oligomers targeting HCV RNA signals with tissue culture-based replication and translation assays. These assays will be used to examine the efficacy and possible toxicity of the PMOs. PMOs are analogs of short DNA oligomers with modified sugar and phosphate moieties in the nucleotides, resulting in high specific binding and complete resistance to nucleases in the host. PMOs have been used to inhibit the movement of scanning ribosomes. Their safety, efficacy, and bioavailability make these compounds great candidates for clinical applications. No small animal models are available to study HCV. We will initially evaluate a panel of PMOs in tissue culture replication and translation models. We will use a transgenic mouse model to evaluate the safety and efficacy of these compounds in animals. The proposed research, if successful, would lead to a application for Phase II funding to bring the use of PMOs into the HCV drug market and provide a well-tolerated, inexpensive alternative to current HCV treatments. [unreadable] [unreadable] [unreadable]